Antibiotic resistant infection, catastrophic and costly, is an increasingly frequent complication of major surgery, trauma, and organ transplantation, and limits the use of biomaterial devices. Infection has been a principal barrier to the successful use of the total artificial heart, and for those in development and early use (e.g., ventricular assist devices and totally implantable artificial hearts), for xeno-transplants and engineered tissues. The emergence of methacillin and vancomycin resistant strains and of a large immuno- compromised and AIDS population, adds troublesome magnitude to the surgical infections disease problem. We report that pooled human immunoglobulin (IgG) preparations (natural polyclonal antibodies), delivered locally, to wounds and damaged tissues, or as biomaterial coatings, in the proximity of contaminating Staphylococcus aureus and Pseudomonas aeruginosa are highly effective in preventing infections in the presence or absence of biomaterials in four animal models in two species. Our hypothesis is that antibody preparations delivered locally to surgical and traumatic wounds, or on biomaterial surfaces (including engineered tissues) at the time of surgery, will prevent infection by enhancing opsonization, phagocytosis, and bacterial killing before antibiotic resistant and biofilm type infections are established. Contemporary pooled human IgG contains a repertoire of antibodies to current and evolving antibiotic resistant strains of bacteria. The studies we present of PLI are the first to demonstrate that the direct application of IgG may be utilized to prevent surgical wound and biomaterial infection. The pre-clinical studies we now propose are expected to further secure proof of concept in anticipation of human clinical trials by expanded investigation of (i) therapeutic dose range responses, for local application, (ii) time course studies, (iii) representative pathogens including antibiotic resistant strains, and (iv) biomaterial responses. (Aims 1 and 2). The mechanisms complement activation, blocking of adhesion, opsonization and phagocytosis) of IgG antimicrobial activity will be characterized in Aim 3. There are 25 million surgeries annually in the U.S. of which four million are at high risk for infection. PLI, based on sound immunologic principals and proof of concept studies, represents a novel, but simple, cost effective strategy and opportunity for effective broad spectrum prophylaxis and therapy, even in the presence of emerging antibiotic resistant pathogens, immunocompromised populations, and biomaterial centered infection.